tbuckley/cabot-search huggingface dataset:
Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure
Authors: Milton Packer, Javed Butler, Cordula Zeller, Stuart J. Pocock, Martina Brueckmann, João Pedro Ferreira, Gerasimos Filippatos, Muhammad Shariq Usman, Faiez Zannad, Stefan D. Anker
Journal: Circulation (2023)

It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy.In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment.From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients.These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug.URL: https://www.gov; Unique identifiers: NCT03057977 and NCT03057951.
Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas
Authors: Nicole Wimberger, Franziska Ober, Göksu Avar, Michael Grau, Wendan Xu, Georg Lenz, Michael P. Menden, Daniel Krappmann
Journal: Blood (2023)

Abstract Constitutive mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activity drives survival of malignant lymphomas addicted to chronic B-cell receptor signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. Although MALT1 scaffolding induces NF-κB–dependent survival signaling, MALT1 protease function is thought to augment NF-κB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-κB transcriptional responses but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and nonenzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease–dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data suggest that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces posttranscriptional upregulation of many genes including NFKBIZ/IκBζ, NFKBID/IκBNS, and ZC3H12A/Regnase-1 in activated B-cell–like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on an mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives posttranscriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in MALT lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and posttranscriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease–selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.
Guideline concordance for timely chest imaging after new presentations of dyspnoea or haemoptysis in primary care: a retrospective cohort study
Authors: Minjoung Monica Koo, Luke T A Mounce, Meena Rafiq, Matthew E J Callister, Hardeep Singh, Gary A Abel, Georgios Lyratzopoulos
Journal: Thorax (2023)

Background Guidelines recommend urgent chest X-ray for newly presenting dyspnoea or haemoptysis but there is little evidence about their implementation. Methods We analysed linked primary care and hospital imaging data for patients aged 30+ years newly presenting with dyspnoea or haemoptysis in primary care during April 2012 to March 2017. We examined guideline-concordant management, defined as General Practitioner-ordered chest X-ray/CT carried out within 2 weeks of symptomatic presentation, and variation by sociodemographic characteristic and relevant medical history using logistic regression. Additionally, among patients diagnosed with cancer we described time to diagnosis, diagnostic route and stage at diagnosis by guideline-concordant status. Results In total, 22 560/162 161 (13.9%) patients with dyspnoea and 4022/8120 (49.5%) patients with haemoptysis received guideline-concordant imaging within the recommended 2-week period. Patients with recent chest imaging pre-presentation were much less likely to receive imaging (adjusted OR 0.16, 95% CI 0.14–0.18 for dyspnoea, and adjusted OR 0.09, 95% CI 0.06–0.11 for haemoptysis). History of chronic obstructive pulmonary disease/asthma was also associated with lower odds of guideline concordance (dyspnoea: OR 0.234, 95% CI 0.225–0.242 and haemoptysis: 0.88, 0.79–0.97). Guideline-concordant imaging was lower among dyspnoea presenters with prior heart failure; current or ex-smokers; and those in more socioeconomically disadvantaged groups. The likelihood of lung cancer diagnosis within 12 months was greater among the guideline-concordant imaging group (dyspnoea: 1.1% vs 0.6%; haemoptysis: 3.5% vs 2.7%). Conclusion The likelihood of receiving urgent imaging concords with the risk of subsequent cancer diagnosis. Nevertheless, large proportions of dyspnoea and haemoptysis presenters do not receive prompt chest imaging despite being eligible, indicating opportunities for earlier lung cancer diagnosis.
Smart hydrogels delivered by high pressure aerosolization can prevent peritoneal adhesions
Authors: Helena Braet, Peter-Paul Fransen, Yong Chen, Simon Van Herck, Remco Mariën, Valérie Vanhoorne, Wim Ceelen, Annemieke Madder, Steven Ballet, Richard Hoogenboom, Bruno De Geest, Anne Hoorens, Patricia Y.W. Dankers, Stefaan C. De Smedt, Katrien Remaut
Journal: Journal of Controlled Release (2023)
A novel EGFR variant EGFRx maintains glioblastoma stem cells through STAT5
Authors: Wei Huang, Jing Li, Hongtao Zhu, Xuhui Qin, Chao Chen, Bing Wang, Jinxia Wei, Yanyang Song, Xia Lu, Zhongyu Li, Wenqing Xia, Aodi He, Lidong Cheng, Xingjiang Yu, Kai Shu, Wei Wang
Journal: Neuro-Oncology (2023)

Glioblastomas are universally lethal brain tumors containing tumor-propagating glioblastoma stem cells (GSCs). EGFR gene amplification or mutation is frequently detected in GBMs and is associated with poor prognosis. However, EGFR variants in GSCs and their role in the maintenance of GSCs and progression of GBM are unclear.
Is alveolar ridge preservation an overtreatment?
Authors: Nikos Mardas, Neil Macbeth, Nikolaos Donos, Ronald Ernst Jung, Anina Nives Zuercher
Journal: Periodontology 2000 (2023)

Abstract The morphology and dimensions of the postextraction alveolar ridge are important for the surgical and restorative phases of implant treatment. Adequate new bone formation and preservation of alveolar ridge dimensions following extraction will facilitate installation of the implant in a restorative position, while preservation of soft tissue contour and volume is essential for an aesthetic and implant‐supported restoration with healthy peri‐implant tissues. Alveolar ridge preservation (ARP) refers to any procedure that aims to: (i) limit dimensional changes in the alveolar ridge after extraction facilitating implant placement without additional extensive bone and soft tissue augmentation procedures (ii) promote new bone formation in the healing alveolus, and (iii) promote soft tissue healing at the entrance of the alveolus and preserve the alveolar ridge contour. Although ARP is a clinically validated and safe approach, in certain clinical scenarios, the additional clinical benefit of ARP over unassisted socket healing has been debated and it appears that for some clinicians may represent an overtreatment. The aim of this critical review was to discuss the evidence pertaining to the four key objectives of ARP and to determine where ARP can lead to favorable outcomes when compared to unassisted socket healing.
FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum
Authors: Sonia Singh, Diana Bradford, Xiaoxue Li, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Lingshan Wang, Hong Zhao, Ye Xiong, Jiang Liu, Rosane Charlab, Jeffrey Kraft, Sachia Khasar, Claudia P. Miller, Donna R. Rivera, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Harpreet Singh, Martha Donoghue
Journal: Clinical Cancer Research (2023)

Abstract On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14–44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.
STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts
Authors: Leonard Buckbinder, David J. St. Jean, Trang Tieu, Brendon Ladd, Brendan Hilbert, Weixue Wang, Jacob T. Alltucker, Samantha Manimala, Gregory V. Kryukov, Natasja Brooijmans, Gregory Dowdell, Philip Jonsson, Michael Huff, Angel Guzman-Perez, Erica L. Jackson, Marcus D. Goncalves, Darrin D. Stuart
Journal: Cancer Discovery (2023)

Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models. These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release. See related commentary by Kearney and Vasan, p. 2313. This article is featured in Selected Articles from This Issue, p. 2293.
Motoric Cognitive Risk Syndrome and Traffic Incidents in Older Drivers in Japan
Authors: Satoshi Kurita, Takehiko Doi, Kenji Harada, Osamu Katayama, Masanori Morikawa, Chiharu Nishijima, Kazuya Fujii, Yuka Misu, Ryo Yamaguchi, Georg von Fingerhut, Daisuke Kakita, Hiroyuki Shimada
Journal: JAMA Network Open (2023)

To prevent motor vehicle collisions by older drivers, the increased risk of collisions should be considered early. Cognitive decline increases the risk of car collisions. Motoric cognitive risk syndrome (MCR), characterized by the presence of cognitive concerns and slow gait, can be assessed conveniently and is useful to assess the risk of dementia.To examine the association between MCR assessment findings and car collisions among older drivers in Japan.This cross-sectional study used data from a community-based cohort study, the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes, conducted in Japan from 2015 to 2018. Participants were community-dwelling older adults aged at least 65 years. Data were analyzed from February to March 2023.MCR was defined as having subjective memory concerns (SMC) and slow gait. Participants were classified into 4 groups: no SMC or slow gait, only SMC, only slow gait, and MCR.Participants were asked about the experience of car collisions during the last 2 years and near-miss traffic incidents during the previous year through face-to-face interviews. Odds of experiencing a collision or near-miss traffic incident were assessed using logistic regression.Among a total of 12 475 participants, the mean (SD) age was 72.6 (5.2) years, and 7093 (56.9%) were male. The group with only SMC and the group with MCR showed a higher proportion of both car collisions and near-miss traffic incidents than the other groups (adjusted standardized residuals > 1.96; P < .001). Logistic regression analysis showed the only SMC and MCR groups had increased odds of car collisions (only SMC group: odds ratio [OR], 1.48; 95% CI, 1.27-1.72; MCR group: OR, 1.73; 95% CI, 1.39-2.16) and near-miss traffic incidents (only SMC group: OR, 2.07; 95% CI, 1.91-2.25; MCR group: OR, 2.13; 95% CI, 1.85-2.45) after adjusting for confounding factors. After stratifying MCR assessments by objective cognitive impairment, significant associations were still observed. In the only slow gait group, objective cognitive impairment was associated with increased odds of car collisions (OR, 1.96; 95% CI, 1.17-3.28).In this cross-sectional study of community-dwelling older drivers in Japan, SMC and MCR were associated with car collisions and near-miss traffic incidents independent from objective cognitive impairment. Future studies should examine the mechanism of these associations in more detail.
Evaluating human milk as a drug delivery vehicle for clofazimine to premature infants
Authors: Ellie Ponsonby-Thomas, Malinda Salim, Laura D. Klein, Andrew J. Clulow, Susi Seibt, Ben J. Boyd
Journal: Journal of Controlled Release (2023)

Human milk is proposed as a drug delivery vehicle suitable for use in neonatal patients. Clofazimine, traditionally used for the treatment of leprosy and tuberculosis, is emerging as a treatment for cryptosporidiosis in infants, however its poor aqueous solubility has led to its commercial formulation as a waxy lipid formulation in a capsule, a format that is not suitable for infants. In this study, the evaluation of pasteurised human milk for the delivery of clofazimine was investigated using an in vitro lipolysis model to simulate gastric and intestinal digestion. The total lipid composition of the human milk was characterised alongside the liberated fatty acid species following digestion for comparison to alternative lipid-based delivery systems. Small-angle X-ray scattering was used to measure the presence of crystalline clofazimine during digestion and hence the extent of drug solubilisation. High-performance liquid chromatography was used to quantify the mass of clofazimine solubilised per gram of human milk fat (drug-to-fat ratio) in digested and undigested human milk. The digestion process was essential for the solubilisation of clofazimine, with digested human milk solubilising a sufficient dose of clofazimine for treatment of a premature infant. Human milk solubilised the clofazimine to a greater extent than bovine milk and infant formula during digestion, most likely as a result of differing lipid composition and increased long-chain fatty acid concentrations. These findings show that human milk enhances the solubility of clofazimine as a model drug and may be a suitable drug delivery vehicle for infant populations requiring therapeutic treatment.
Sepsis Prediction Model for Determining Sepsis vs SIRS, qSOFA, and SOFA
Authors: Adam R. Schertz, Kristin M. Lenoir, Alain G. Bertoni, Beverly J. Levine, Morgana Mongraw-Chaffin, Karl W. Thomas
Journal: JAMA Network Open (2023)

The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not undergone validation against existing sepsis prediction tools, such as Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick Sepsis-Related Organ Failure Asessement (qSOFA).To assess the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA.This retrospective cohort study included all adults admitted to 5 acute care hospitals in a single US health system between June 5, 2019, and December 31, 2020. Data analysis was conducted from March 2021 to February 2023.A sepsis event was defined as receipt of 4 or more days of antimicrobials, blood cultures collected within ±48 hours of initial antimicrobial, and at least 1 organ dysfunction as defined by the organ dysfunction criteria optimized for the electronic health record (eSOFA). Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order.Of 60 507 total admissions, 1663 (2.7%) met sepsis criteria, with 1324 electronic health record-confirmed sepsis (699 [52.8%] male patients; 298 [22.5%] Black patients; 46 [3.5%] Hispanic/Latinx patients; 945 [71.4%] White patients), 339 COVID-19 sepsis (183 [54.0%] male patients; 98 [28.9%] Black patients; 36 [10.6%] Hispanic/Latinx patients; and 189 [55.8%] White patients), and 58 844 (97.3%; 26 632 [45.2%] male patients; 12 698 [21.6%] Black patients; 3367 [5.7%] Hispanic/Latinx patients; 40 491 White patients) did not meet sepsis criteria. The median (IQR) age was 63 (51 to 73) years for electronic health record-confirmed sepsis, 69 (60 to 77) years for COVID-19 sepsis, and 60 (42 to 72) years for nonsepsis admissions. Within the vendor recommended threshold PSS range of 5 to 8, PSS of 8 or greater had the highest balanced accuracy for classifying a sepsis admission at 0.79 (95% CI, 0.78 to 0.80). Change in SOFA score of 2 or more had the highest sensitivity, at 0.97 (95% CI, 0.97 to 0.98). At a PSS of 8 or greater, median (IQR) time to score positivity from time zero was 68.00 (6.75 to 605.75) minutes. For SIRS, qSOFA, and SOFA, median (IQR) time to score positivity was 7.00 (-105.00 to 08.00) minutes, 74.00 (-22.25 to 599.25) minutes, and 28.00 (-108.50 to 134.00) minutes, respectively.In this cohort study of hospital admissions, balanced accuracy of the SPM outperformed other models at higher threshold PSS; however, application of the SPM in a clinical setting was limited by poor timeliness as a sepsis screening tool as compared to SIRS and SOFA.
Clinical Features and Prognoses of Patients With Breast Cancer Who Underwent Surgery
Authors: Gang Liu, Xiangyi Kong, Qichen Dai, Han Cheng, Jing Wang, Jidong Gao, Yipeng Wang
Journal: JAMA Network Open (2023)

Breast cancer (BC) remains a pervasive malignant neoplasm worldwide, with increasing incidence. However, there are a scarcity of studies examining the clinical characteristics and prognosis of Chinese patients with BC who have undergone surgery.